A novel role of astrocyte elevated gene-1 (AEG-1) in regulating nonalcoholic steatohepatitis (NASH)

Jyoti Srivastava, Chadia L. Robertson, Kareem Ebeid, Mikhail Dozmorov, Devaraja Rajasekaran, Rachel Mendoza, Ayesha Siddiq, Maaged A. Akiel, Nidhi Jariwala, Xue Ning Shen, Jolene J. Windle, Mark A. Subler, Nitai D. Mukhopadhyay, Shah Giashuddin, Shobha Ghosh, Zhao Lai, Yidong Chen, Paul B. Fisher, Aliasger K. Salem, Arun J. SanyalDevanand Sarkar

Resultado de la investigación: Articlerevisión exhaustiva

19 Citas (Scopus)

Resumen

Nonalcoholic steatohepatitis (NASH) is the most prevalent cause of chronic liver disease in the Western world. However, an optimum therapy for NASH is yet to be established, mandating more in-depth investigation into the molecular pathogenesis of NASH to identify novel regulatory molecules and develop targeted therapies. Here, we unravel a unique function of astrocyte elevated gene-1(AEG-1)/metadherin in NASH using a transgenic mouse with hepatocyte-specific overexpression of AEG-1 (Alb/AEG-1) and a conditional hepatocyte-specific AEG-1 knockout mouse (AEG-1ΔHEP). Alb/AEG-1 mice developed spontaneous NASH whereas AEG-1ΔHEP mice were protected from high-fat diet (HFD)-induced NASH. Intriguingly, AEG-1 overexpression was observed in livers of NASH patients and wild-type (WT) mice that developed steatosis upon feeding HFD. In-depth molecular analysis unraveled that inhibition of peroxisome proliferator-activated receptor alpha activity resulting in decreased fatty acid β-oxidation, augmentation of translation of fatty acid synthase resulting in de novo lipogenesis, and increased nuclear factor kappa B–mediated inflammation act in concert to mediate AEG-1-induced NASH. Therapeutically, hepatocyte-specific nanoparticle-delivered AEG-1 small interfering RNA provided marked protection from HFD-induced NASH in WT mice. Conclusion: AEG-1 might be a key molecule regulating initiation and progression of NASH. AEG-1 inhibitory strategies might be developed as a potential therapeutic intervention in NASH patients. (Hepatology 2017;66:466–480).

Idioma originalEnglish (US)
Páginas (desde-hasta)466-480
Número de páginas15
PublicaciónHepatology
Volumen66
N.º2
DOI
EstadoPublished - ago. 2017

ASJC Scopus subject areas

  • Hepatology

Huella

Profundice en los temas de investigación de 'A novel role of astrocyte elevated gene-1 (AEG-1) in regulating nonalcoholic steatohepatitis (NASH)'. En conjunto forman una huella única.

Citar esto